A broad range of biologic and clinical studies of multiple myeloma will be conducted to define the mechanisms of drug resistance. Laboratory research will be integrated with a clinical program using high dose melphalan and total body irradiation (supported by bone marrow transplantation) as a consolidation therapy after VAD-induced remission or as a salvage program for VAD failure. The main clinical goal is to maximize tumor cytoreduction using 2 highly effective and non-cross resistant regimens, so that long term disease control and perhaps cure of this B cell neoplasm can be accomplished. Laboratory studies will define the myeloma tumor genotype and phenotypic features associated with drug resistance and examine relapse in the context of clonal evaluation. In this endeavor, cytometric, cytogenetic and molecular genetic studies will be employed to provide a comprehensive evaluation of myeloma plasma cells during defined stages of the clinical program at diagnosis, in remission and at relapse. The unique therapeutic approach will provide the great opportunity to study fundamentally important areas of myeloma and cancer biology in general, i.e. clonal evaluation, drug resistance and potential obstacles to cure despite supralethal cytotoxic therapy.